tbuckley/cabot-search huggingface dataset:
Bifunctional cancer cell–based vaccine concomitantly drives direct tumor killing and antitumor immunity
Authors: Kok-Siong Chen, Clemens Reinshagen, Thijs A. Van Schaik, Filippo Rossignoli, Paulo Borges, Natalia Claire Mendonca, Reza Abdi, Brennan Simon, David A. Reardon, Hiroaki Wakimoto, Khalid Shah
Journal: Science Translational Medicine (2023)

The administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. Here, we developed a bifunctional whole cancer cell–based therapeutic with direct tumor killing and immunostimulatory roles. We repurposed the tumor cells from interferon-β (IFN-β) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-β–specific receptor and subsequently engineered them to release immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor. These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating cancer-associated fibroblast-expressed platelet-derived growth factor receptor β, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The incorporation of a double kill-switch comprising herpes simplex virus–1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensured the safety of our approach. Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a road map toward clinical translation.
Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial
Authors: Meletios A. Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San-Miguel, Nizar J. Bahlis, Saad Z. Usmani, Neil Rabin, Robert Z. Orlowski, Kenshi Suzuki, Torben Plesner, Sung-Soo Yoon, Dina Ben Yehuda, Paul G. Richardson, Hartmut Goldschmidt, Donna Reece, Tahamtan Ahmadi, Xiang Qin, Wendy Garvin Mayo, Xue Gai, Jodi Carey, Robin Carson, Philippe Moreau
Journal: Journal of Clinical Oncology (2023)

PURPOSE With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS). METHODS POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression. RESULTS Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ≥ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%). CONCLUSION D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).
Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation
Authors: Estibaliz Castillero, Emmett Fitzpatrick, Samuel J. Keeney, Alex M. D’Angelo, Benjamin B. Pressly, Michael T. Simpson, Mangesh Kurade, W. Clinton Erwin, Vivian Moreno, Chiara Camillo, Halley J. Shukla, Vaishali V. Inamdar, Arbi Aghali, Juan B. Grau, Elisa Salvati, Itzhak Nissim, Lubica Rauova, Mark A. Oyama, Stanley J. Stachelek, Chase Brown, Abba M. Krieger, Robert J. Levy, Giovanni Ferrari
Journal: Science Translational Medicine (2023)

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT −/− mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor β1 ( TGF β 1 ) and collagen ( COL1A1 ) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.
Highly synchronized cortical circuit dynamics mediate spontaneous pain in mice
Authors: Weihua Ding, Lukas Fischer, Qian Chen, Ziyi Li, Liuyue Yang, Zerong You, Kun Hu, Xinbo Wu, Xue Zhou, Wei Chao, Peter Hu, Tewodros Mulugeta Dagnew, Daniel M. Dubreuil, Shiyu Wang, Suyun Xia, Caroline Bao, Shengmei Zhu, Lucy Chen, Changning Wang, Brian Wainger, Peng Jin, Jianren Mao, Guoping Feng, Mark T. Harnett, Shiqian Shen
Journal: Journal of Clinical Investigation (2023)

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a “normal” operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain–like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos–expressing neurons and selective activation of GABAergic interneurons significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More important, restoring a “normal” range of neural dynamics through attenuation of pain-induced S1 synchronization alleviated pain-like behavior. These results suggest that spontaneous pain pushed the S1 regional network into a synchronized state, whereas reversal of this synchronization alleviated pain.
Long-Term Exposure to Air Pollution and the Occurrence of Metabolic Syndrome and Its Components in Taiwan
Authors: Yi-Chuan Chen, Wei-Shan Chin, Shih-Chun Pan, Chih-Da Wu, Yue-Liang Leon Guo
Journal: Environmental Health Perspectives (2023)

Background: Metabolic syndrome (MetS), a major contributor to cardiovascular and metabolic diseases, has been linked with exposure to air pollution. However, the relationship between air pollutants and the five components of MetS [abdominal obesity, elevated triglyceride, decreased high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and elevated fasting blood glucose levels], has not been clearly described. Objective: We examined the association between long-term exposure to air pollutants and the occurrence of MetS and its components by using a longitudinal cohort in Taiwan. Methods: The MJ Health Research Foundation is a medical institute that conducts regular physical examinations. The development of MetS, based on a health examination and the medical history of an MJ cohort of 93,771 participants who were enrolled between 2006 and 2016 and had two or more examinations, was compared with estimated exposure to air pollutants in the year prior to health examination. The exposure levels to fine particulate matter [PM with an aerodynamic diameter of ≤2.5μm (PM2.5)] and nitrogen dioxide (NO2) in the participants’ residential areas were estimated using a hybrid Kriging/land-use regression (LUR) model executed using the XGBoost algorithm and a hybrid Kriging/LUR model, respectively. Cox regression with time-dependent covariates was conducted to estimate the effects of annual air pollutant exposure on the risk of MetS and its components. Results: During the average follow-up period of 3.4 y, the incidence of MetS was 38.1/1,000 person-years. After mutual adjustment and adjustments for potential covariates, the results indicated that every 10-μg/m3 increase in annual PM2.5 concentration was associated with an increased risk of abdominal obesity [adjusted hazard ratio (aHR)=1.07; 95% confidence interval (CI): 1.01, 1.14], hypertriglyceridemia (aHR=1.17; 95% CI: 1.11, 1.23), low HDL-C (aHR=1.09; 95% CI: 1.02, 1.17), hypertension (aHR=1.15; 95% CI: 1.09, 1.21), and elevated fasting blood glucose (aHR=1.15; 95% CI: 1.10, 1.20). Furthermore, PM2.5 and NO2 may increase the risk of developing MetS among people who already “have” some components of MetS. Discussion: Our findings suggest that in apparently healthy adults undergoing physical examination, exposure to PM2.5 and NO2 might be associated with the occurrence of MetS and its components. https://doi.org/10.1289/EHP10611
Interactive Effects of Molecular, Therapeutic, and Patient Factors on Outcome of Diffuse Low-Grade Glioma
Authors: Shawn L. Hervey-Jumper, Yalan Zhang, Joanna J. Phillips, Ramin A. Morshed, Jacob S. Young, Lucie McCoy, Marisa Lafontaine, Tracy Luks, Simon Ammanuel, Sofia Kakaizada, Andrew Egladyous, Andrew Gogos, Javier Villanueva-Meyer, Anny Shai, Gayathri Warrier, Terri Rice, Jason Crane, Margaret Wrensch, John K. Wiencke, Mariza Daras, Nancy Ann Oberheim Bush, Jennie W. Taylor, Nicholas Butowski, Jennifer Clarke, Susan Chang, Edward Chang, Manish Aghi, Philip Theodosopoulos, Michael McDermott, Asgeir S. Jakola, Vasileios K. Kavouridis, Noah Nawabi, Ole Solheim, Timothy Smith, Mitchel S. Berger, Annette M. Molinaro
Journal: Journal of Clinical Oncology (2023)

PURPOSE In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible. METHODS In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR. RESULTS Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) &gt; 4.6 mL and those with preoperative TV &gt; 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV &gt; 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume &gt; 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis. CONCLUSION Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma. [Media: see text]
Prognostic value and oncogenic landscape of <i>TP53</i> alterations in adult and pediatric T-ALL
Authors: Mathieu Simonin, Guillaume P. Andrieu, Rudy Birsen, Marie Balsat, Guillaume Hypolite, Lucien Courtois, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Françoise Huguet, Yves Chalandon, Yannick Le Bris, Elizabeth Macintyre, Virginie Gandemer, Arnaud Petit, Philippe Rousselot, André Baruchel, Didier Bouscary, Olivier Hermine, Nicolas Boissel, Vahid Asnafi
Journal: Blood (2023)
Association of fracture incidence in children with the development of food allergy: A Korean nationwide birth cohort study
Authors: Rosie Kwon, Youn Ho Shin, Jae Il Shin, So Min Kang, Jimin Hwang, Jung U. Shin, Hyungrye Noh, Chan Yeong Heo, Ai Koyanagi, Louis Jacob, Lee Smith, Jonas F. Ludvigsson, Stephen Turner, Ju‐Young Shin, Han Eol Jeong, Jung‐Hyun Kim, Sang Youl Rhee, Chanyang Min, Dong In Suh, Min Ji Koo, Katrina Abuabara, Sunyeup Kim, Seung Won Lee, Dong Keon Yon, Seong Ho Cho
Journal: Allergy (2023)

Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment
Authors: Kelly von Beck, Troy von Beck, P. Brent Ferrell, Alexander G. Bick, Ashwin Kishtagari
Journal: Blood Cancer Journal (2023)

Clonal hematopoiesis (CH) is the age-related expansion of hematopoietic stem cell clones caused by the acquisition of somatic point mutations or mosaic chromosomal alterations (mCAs). Clonal hematopoiesis caused by somatic mutations has primarily been associated with increased risk of myeloid malignancies, while mCAs have been associated with increased risk of lymphoid malignancies. A recent study by Niroula et al. challenged this paradigm by finding a distinct subset of somatic mutations and mCAs that are associated with increased risk of lymphoid malignancy. CH driven by these mutations is termed lymphoid clonal hematopoiesis (L-CH). Unlike myeloid clonal hematopoiesis (M-CH), L-CH has the potential to originate at both stem cells and partially or fully differentiated progeny stages of maturation. In this review, we explore the definition of L-CH in the context of lymphocyte maturation and lymphoid malignancy precursor disorders, the evidence for L-CH in late-onset autoimmunity and immunodeficiency, and the development of therapy-related L-CH following chemotherapy or hematopoietic stem cell transplantation.
Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management
Authors: Mrinal M. Patnaik, Ayalew Tefferi
Journal: American Journal of Hematology (2023)

Abstract Disease Overview Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with &lt;20% blasts in the blood and bone marrow. Diagnosis aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN‐NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN‐ring sideroblasts‐thrombocytosis (MDS/MPN‐RS‐T), and aCML. Mutations and Karyotype Cytogenetic abnormalities are seen in 40–50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1 , SETBP1 , ETNK1 , and EZH2 whereas MDS/MPN‐NOS can be further stratified by mutational profiles into CMML‐like, MDS/MPN‐RS‐T‐like, aCML‐like, TP35 ‐mutated, and “others”, respectively. Risk Stratification The Mayo Clinic aCML model stratifies patients based on age &gt;67 years, hemoglobin &lt;10 g/dl, and the presence of TET2 mutations into low‐risk (0–1 points) and high‐risk (&gt;2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN‐NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS‐R. Treatment Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.
An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis
Authors: Shuang Wang, Kenneth Li, Eliana Pickholz, Ross Dobie, Kylie P. Matchett, Neil C. Henderson, Chris Carrico, Ian Driver, Martin Borch Jensen, Li Chen, Mathieu Petitjean, Dipankar Bhattacharya, Maria I. Fiel, Xiao Liu, Tatiana Kisseleva, Uri Alon, Miri Adler, Ruslan Medzhitov, Scott L. Friedman
Journal: Science Translational Medicine (2023)

Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3–neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.
Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of <i>Candida albicans</i>
Authors: Shraddheya Kumar Patel, Satya Ranjan Sahu, Bhabasha Gyanadeep Utkalaja, Swagata Bose, Narottam Acharya
Journal: Gut Microbes (2023)

Candida albicans is a pathobiont that inflicts serious bloodstream fungal infections in individuals with compromised immunity and gut dysbiosis. Genomic diversity in the form of copy number alteration, ploidy variation, and loss of heterozygosity as an adaptive mechanism to adverse environments is frequently observed in C. albicans. Such genomic variations also confer a varied degree of fungal virulence and drug resistance, yet the factors propelling these are not completely understood. DNA polymerase delta (Polδ) is an essential replicative DNA polymerase in the eukaryotic cell and is yet to be characterized in C. albicans. Therefore, this study was designed to gain insights into the role of Polδ, especially its non-essential subunit Pol32, in the genome plasticity and life cycle of C. albicans. PCNA, the DNA clamp, recruits Polδ to the replication fork for processive DNA replication. Unlike in Saccharomyces cerevisiae, the PCNA interaction protein (PIP) motif of CaPol32 is critical for Polδ's activity during DNA replication. Our comparative genetic analyses and whole-genome sequencing of POL32 proficient and deficient C. albicans cells revealed a critical role of Pol32 in DNA replication, cell cycle progression, and genome stability as SNPs, indels, and repeat variations were largely accumulated in pol32 null strain. The loss of pol32 in C. albicans conferred cell wall deformity; Hsp90 mediated azoles resistance, biofilm development, and a complete attenuation of virulence in an animal model of systemic candidiasis. Thus, although Pol32 is dispensable for cell survival, its function is essential for C. albicans pathogenesis; and we discuss its translational implications in antifungal drugs and whole-cell vaccine development.
Angiomotin and angiostatin as asthma biomarkers: Implications for the regulation of airway remodeling and inflammation
Authors: Pureun‐Haneul Lee, SeonMuk Choi, MinHyeok An, DaYeon Hwang, Shinhee Park, Ae Rin Baek, An‐Soo Jang
Journal: Allergy (2023)

Appendix S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Bending the patient safety curve: how much can AI help?
Authors: David C. Classen, Christopher Longhurst, Eric J. Thomas
Journal: npj Digital Medicine (2023)

This paper reviews the current state of patient safety and the application of artificial intelligence (AI) techniques to patient safety. This paper defines patient safety broadly, not just inpatient care but across the continuum of care, including diagnostic errors, misdiagnosis, adverse events, injuries, and measurement issues. It outlines the major current uses of AI in patient safety and the relative adoption of these techniques in hospitals and health systems. It also outlines some of the limitations of these AI systems and the challenges with evaluation of these systems. Finally, it outlines the importance of developing a proactive agenda for AI in healthcare that includes marked increased funding of research and evaluation in this area.